Failure of presented, non-dominant self epitope to induce tolerance: implications for autoimmune diseases

It has been observed that a hierarchy exists among epitopes such that fewer epitopes are actually involved in the induction of T cell response and tolerance than there are epitopes available in a given antigen. Some epitopes which are "cryptic" for immune activity within the protein, are nevertheless able to elicit a response if administered alone and can also be used to by-pass tolerance. We report that tolerance to a self protein shows the same phenomenon seen for non self proteins. In fact, we elicit a proliferative response toward a predicted minor cryptic epitope, to which animals are clearly not self-tolerant. The minor epitope escapes the induction of tolerance to self proteins more easily than the major epitopes, since we cannot elicit proliferative response to the major epitope. A striking feature of our results however is that lack of self tolerance to the minor epitope appears as not being due to the failure of presentation of this epitope in normal, healthy animals.